Methods for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor

ABSTRACT

Methods for reducing or preventing transplant rejection in the eye of an individual are described, comprising: a) performing an ocular transplant procedure; and b) implanting in the eye a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 09/997,094, filed Nov.28, 2001, now U.S. Pat. No. 6,699,493. This application claims priorityto U.S. Provisional Application Ser. No. 60/250,023, filed Nov. 29,2000, titled “Methods for Preventing Transplant Rejection in the Eye andIntraocular Implants for Use Thereof” and U.S. Provisional ApplicationSer. No. 60/298,253, filed Jun. 12, 2001, titled “IntraocularDexamethasone Deliver System for Corneal Transplantation in AnimalModel.” Both of these Provisional applications are incorporated hereinby reference.

TECHNICAL FIELD

This invention relates to the field of transplantation, in particulartransplantation of components of the eye, and methods for preventingtransplant rejection.

BACKGROUND ART

Certain conditions and diseases of the eye, such as corneal failure,keratoconus, corneal dystrophies, scarring, age related maculardegeneration (AMD) and retinitis pigmentosa, have been treated usingocular transplant procedures such as corneal and retinal pigmentepithelial (RPE) transplants. Transplant rejection is one of theproblems which may arise from transplant procedures (Enzmann V et al.(1998). “Immunological problems of transplantation into the subretinalspace.” Acta Anat (Basel). 162(2-3): 178-83). In spite of the overallsuccess with corneal transplants, a substantial percentage of cornealgrafts experience at least one rejection episode (PCT/US97/21393).

One of the problems with present immunosuppressive drug therapy is theinability to achieve adequate intraocular drug concentrations. Systemicimmunosuppression may require prolonged exposure to high plasmaconcentrations so that therapeutic levels can be achieved in the eye.Overall drug delivery to the eye may be poor due to the short drugplasma half-life limiting exposure into intraocular tissues. Inaddition, this may turn lead to numerous negative side effects.

There is a continued need for improved intraocular sustained releasedrug therapies for patients following ocular transplant procedures.

All references cited in this patent are incorporated herein by referencein their entirety.

DISCLOSURE OF THE INVENTION

One embodiment of the present invention provides a method for reducingor preventing transplant rejection in the eye of an individual, wherethe method comprises: a) performing an ocular transplant procedure; andb) implanting in the eye a bioerodible drug delivery system comprisingan immunosuppressive agent and a bioerodible polymer.

Another embodiment of the invention provides a method for reducing orpreventing transplant rejection in the eye of an individual, where themethod comprises: a) performing an ocular transplant procedure; and b)implanting a solid body into the eye, said body comprising particles ofan immunosuppressive agent entrapped within a bioerodible polymer,whereby said agent is released from the body by erosion of the polymer.

Another embodiment of the invention provides a method which includesplacing in an eye of an individual a bioerodible drug delivery system,where the bioerodible drug delivery system includes an immunosuppressiveagent and a bioerodible polymer; and where the eye of the individual hasundergone or is undergoing an ocular transplant procedure. This methodmay be used to reduce or prevent transplant rejection.

Another embodiment of the invention provides a kit comprising: a) abioerodible drug delivery system comprising an immunosuppressive agentand a bioerodible polymer, wherein the drug delivery system is designedto be implanted in the eye; and b) instructions for use. This kit may beused to reduce or prevent transplant rejection.

MODES FOR CARRYING OUT THE INVENTION

Definitions

An “ocular transplant procedure,” as used herein, refers to anytransplant procedure performed in the eye. Non-limiting examples ofocular transplant procedures include, but are not limited to, retinalpigment epithelium (RPE) transplant and cornea transplant. It includesautograft, allograft and xenograft transplant procedures.

“Immunosuppressive agent,” “agent,” “immunosuppressive drug,” and“drug,” are used interchangeably herein, and refer to any agent whichinhibits or prevents an immune response against the transplanted tissuefollowing a transplant procedure. Exemplary agents include, but are notlimited to, dexamethasone, cyclosporin A, azathioprine, brequinar,gusperimus, 6-mercaptopurine, mizoribine, rapamycin, tacrolimus(FK-506), folic acid analogs (e.g., denopterin, edatrexate,methotrexate, piritrexim, pteropterin, Tomudex®, trimetrexate), purineanalogs (e.g., cladribine, fludarabine, 6-mercaptopurine, thiamiprine,thiaguanine), pyrimidine analogs (e.g., ancitabine, azacitidine,6-azauridine, carmofur, cytarabine, doxifluridine, emitefur,enocitabine, floxuridine, fluorouracil, gemcitabine, tegafur),fluocinolone, triaminolone, anecortave acetate, flurometholone,medrysone, and prednislone.

An “implant” and a “drug delivery system,” are used interchangeablyherein, and include any bioerodible device for implantation in the eyewhich is capable of delivering a therapeutic level of drug to the eye.

To “implant” to “place” and to “insert” are equivalent as used in thispatent and mean to place an object in the desired site by any meanscapable of placing the object at that site.

By “therapeutic level” is meant a level of drug sufficient to prevent,inhibit, or reduce the level of transplant rejection in the eye.

The term “bioerodible polymer” refers to polymers which degrade in vivo,and wherein erosion of the polymer over time is required to achieve theagent release kinetics according to the invention. Specifically,hydrogels such as methylcellulose which act to release drug throughpolymer swelling are specifically excluded from the term “bioerodiblepolymer”. The terms “bioerodible” and “biodegradable” are equivalent andare used interchangeably in this patent.

An “individual” is a vertebrate, preferably mammal, more preferably ahuman. Mammals include, but are not limited to, humans, rodents, sportanimals and pets, such as rats, dogs, and horses.

Methods for Reducing or Preventing Transplant Rejection

Intraocular immunosuppressive drug delivery systems made of abiodegradable polymer matrix are provided which can release drug loadsover various programmed time periods. When inserted into the eye thesedrug delivery systems provide therapeutic levels of immunosuppressiveagent for reducing or preventing transplant rejection.

Accordingly, one embodiment of the present invention provides a methodfor reducing or preventing transplant rejection in the eye of anindividual, comprising: performing an ocular transplant procedure; andimplanting in the eye a bioerodible drug delivery system comprising animmunosuppressive agent and a bioerodible polymer.

In another embodiment of the invention, a method for reducing orpreventing transplant rejection in the eye of an individual is provided,comprising: performing an ocular transplant procedure; and implanting asolid body into the eye, said body comprising particles of animmunosuppressive agent entrapped within a bioerodible polymer, wherebysaid agent is released from the body by erosion of the polymer.

Ocular transplant procedures which may be used with the methods of theinvention include, but are not limited to, cornea transplant and RPEtransplant. Methods for performing these transplant procedures are wellknown in the art. Methods for performing RPE transplants are describedin, for example, U.S. Pat. Nos. 5,962,027, 6,045,791, and 5,941,250 andin Eye Graefes Arch Clin Exp Opthalmol 1997 March; 235(3):149-58;Biochem Biophys Res Commun 2000 February. 24; 268(3): 842-6; OpthalmicSurg 1991 February; 22(2): 102-8. Methods for performing cornealtransplants are described in, for example, U.S. Pat. No. 5,755,785, andin Eye 1995; 9 (Pt 6 Su):6-12; Curr Opin Opthalmol 1992 August; 3 (4):473-81; Ophthalmic Surg Lasers 1998 April; 29 (4): 305-8; Ophthalmology2000 April; 107 (4): 719-24; and Jpn J Ophthalmol 1999November-December; 43(6): 502-8. Exemplary methods for corneal and RPEtransplantation in animal models are described in Examples 1, 4 and 5below. In a preferred embodiment, the ocular transplant procedure is acornea transplant. In another preferred embodiment, the oculartransplant procedure is an RPE procedure.

The drug delivery system may be implanted at various sites in the eye,depending on the size, shape and formulation of the implant, the type oftransplant procedure, etc. Suitable sites include but are not limited tothe anterior chamber, anterior segment, posterior chamber, posteriorsegment, vitreous cavity, suprachoroidal space, subconjunctiva,episcleral, intraconeal, epicorneal and sclera. In a preferredembodiment, the drug delivery system is placed in the anterior chamberof the eye. In another preferred embodiment, the drug delivery system isplaced in the vitreous cavity.

The implants may be inserted into the eye by a variety of methods,including placement by forceps or by trocar following making an incisionin the sclera (for example, a 2-3 mm incision) or other suitable site.In some cases, the implant may be able to be placed by trocar withoutmaking a separate incision, but instead by punching a hole directly intothe eye with the trocar. The method of placement may influence the drugrelease kinetics. For example, implanting the device into the vitreouswith a trocar may result in placement of the device deeper within thevitreous than placement by forceps, which may result in the implantbeing closer to the edge of the vitreous. The location of the implanteddevice may influence the concentration gradients of drug surrounding thedevice, and thus influence the release rates (e.g., a device placedcloser to the edge of the vitreous may result in a slower release rate).

U.S. Pat. No. 5,869,079 further describes locations for intraocularimplants and methods for insertion (see in particular col. 6-7).

In one embodiment, the implant delivers the immunosuppressive agent forat least about 5 days. In other embodiments, the implant delivers theimmunosuppressive agent for at least about one week, at least about 2weeks, at least about 3 weeks, at least about four weeks, at least aboutfive weeks, at least about six weeks, at least about seven weeks, atleast about eight weeks, at least about nine weeks, at least about 10weeks, and at least about 12 weeks. The preferred duration of drugrelease may be determined by the type of transplant, the medical historyof the patient, etc. In one embodiment, drug release may occur for up to6 months, or one year, or longer. In one embodiment, more than oneimplant may be sequentially implanted into the vitreous in order tomaintain drug concentrations for even longer periods. In one embodiment,more than one implant may be sequentially implanted into the eye inorder to maintain therapeutic drug concentrations for longer periods.Co-owned U.S. patent application Ser. No. 09/693,008, titled “MethodsFor Treating Inflammation-Mediated Conditions of the Eye,” to Wong etal. filed October. 20, 2000, which is expressly incorporated herein byreference in its entirety, further describes implants and methods formaking the implants which can achieve and maintain particular drugconcentrations for programmed extended periods of time.

The methods of the invention are preferably performed on vertebrates,preferably mammal, more preferably a human. Mammals include, but are notlimited to, humans, rodents, sport animals and pets, such as rats, dogsand horses.

Implants

The formulation of the implants for use in the invention may varyaccording to the preferred drug release profile, the particularimmunosuppressive agent used, the transplant procedure, the medicalhistory of the patient and other factors affecting the formulation.

The implants of the invention are formulated with particles of theimmunosuppressive agent associated with the bioerodible polymer matrix.In a preferred embodiment the immunosuppressive agent is entrappedwithin the bioerodible polymer matrix. Without being bound by theory, wehypothesize that release of the agent is achieved by erosion of thepolymer followed by exposure of previously entrapped agent particles tothe eye, and subsequent dissolution and release of agent. The releasekinetics achieved by this form of drug release are different than thatachieved through formulations which release drug through polymerswelling, such as with hydrogels such as methylcellulose. In that case,the drug is not released through polymer erosion, but through polymerswelling, which release drug as liquid diffuses through the pathwaysexposed. The parameters which may determine the release kinetics includethe size of the drug particles, the water solubility of the drug, theratio of drug to polymer, the method of manufacture, the surface areaexposed, and the erosion rate of the polymer.

In a preferred embodiment the immunosuppressive agent is selected fromthe group consisting of dexamethasone, cyclosporin A, azathioprine,brequinar, gusperimus, 6-mercaptopurine, mizoribine, rapamycin,tacrolimus (FK-506), folic acid analogs (e.g., denopterin, edatrexate,methotrexate, piritrexim, pteropterin, Tomudex®, trimetrexate), purineanalogs (e.g., cladribine, fludarabine, 6-mercaptopurine, thiamiprine,thiaguanine), pyrimidine analogs (e.g., ancitabine, azacitidine,6-azauridine, carmofur, cytarabine, doxifluridine, emitefur,enocitabine, floxuridine, fluorouracil, gemcitabine, tegafur)fluocinolone, triaminolone, anecortave acetate, fluorometholone,medrysone, and prednislone. In a preferred embodiment, theimmunosuppressive agent is dexamethasone. In another preferredembodiment, the immunosuppressive agent is cyclosporin A. In anotherembodiment, the bioerodible implant comprises more than oneimmunosuppressive agent.

The implants may further comprise one or more additional therapeuticagents, such as antibiotics or antiinflammatory agents. Specificantibiotics include, but are not limited to:

Antibacterial Antibiotics:

Aminoglycosides (e.g., amikacin, apramycin, arbekacin, bambermycins,butirosin, dibekacin, dihydrostreptomycin, fortimicin(s), gentamicin,isepamicin, kanamycin, micronomicin, neomycin, neomycin undecylenate,netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin,streptomycin, tobramycin, trospectomycin), amphenicols (e.g.,azidamfenicol, chloramphenicol, florfenicol, thiamphenicol), ansamycins(e.g., rifamide, rifampin, rifamycin sv, rifapentine, rifaximin),β-lactams (e.g., carbacephems (e.g., loracarbef), carbapenems (e.g.,biapenem, imipenem, meropenem, panipenem), cephalosporins (e.g.,cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin,cefcapene pivoxil, cefclidin, cefdinir, cefditoren, cefepime, cefetamet,cefixime, cefinenoxime, cefodizime, cefonicid, cefoperazone, ceforanide,cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome,cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin, ceftazidime,cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin,cephaloridine, cephalosporin, cephalothin, cephapirin sodium,cephradine, pivcefalexin), cephamycins (e.g., cefbuperazone,cefinetazole, cefminox, cefotetan, cefoxitin), monobactams (e.g.,aztreonam, carumonam, tigemonam), oxacephems, flomoxef, moxalactam),penicillins (e.g., amdinocillin, amdinocillin pivoxil, amoxicillin,ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin,bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium,carbenicillin, carindacillin, clometocillin, cloxacillin, cyclacillin,dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin,lenampicillin, metampicillin, methicillin sodium, mezlocillin, nafcillinsodium, oxacillin, penamecillin, penethamate hydriodide, penicillin gbenethamine, penicillin g benzathine, penicillin g benzhydrylamine,penicillin g calcium, penicillin g hydrabamine, penicillin g potassium,penicillin g procaine, penicillin n, penicillin o, penicillin v,penicillin v benzathine, penicillin v hydrabamine, penimepicycline,phenethicillin potassium, piperacillin, pivampicillin, propicillin,quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin,ticarcillin), other (e.g., ritipenem), lincosamides (e.g., clindamycin,lincomycin), macrolides (e.g., azithromycin, carbomycin, clarithromycin,dirithromycin, erythromycin, erythromycin acistrate, erythromycinestolate, erythromycin glucoheptonate, erythromycin lactobionate,erythromycin propionate, erythromycin stearate, josamycin, leucomycins,midecamycins, miokamycin, oleandomycin, primycin, rokitamycin,rosaramicin, roxithromycin, spiramycin, troleandomycin), polypeptides(e.g., amphomycin, bacitracin, capreomycin, colistin, enduracidin,enviomycin, fusafungine, gramicidin s, gramicidin(s), mikamycin,polymyxin, pristinamycin, ristocetin, teicoplanin, thiostrepton,tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomycin,virginiamycin, zinc bacitracin), tetracyclines (e.g., apicycline,chlortetracycline, clomocycline, demeclocycline, doxycycline,guamecycline, lymecycline, meclocycline, methacycline, minocycline,oxytetracycline, penimepicycline, pipacycline, rolitetracycline,sancycline, tetracycline), and others (e.g., cycloserine, mupirocin,tuberin).

Synthetic Antibacterials:

2,4-Diaminopyrimidines (e.g., brodimoprim, tetroxoprim, trimethoprim),nitrofurans (e.g., furaltadone, furazolium chloride, nifuradene,nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoinol,nitrofurantoin), quinolones and analogs (e.g., cinoxacin, ciprofloxacin,clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine,grepafloxacin, lomefloxacin, miloxacin, nadifloxacin, nalidixic acid,norfloxacin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin,pipemidic acid, piromidic acid, rosoxacin, rufloxacin, sparfloxacin,temafloxacin, tosufloxacin, trovafloxacin), sulfonamides (e.g., acetylsulfamethoxypyrazine, benzylsulfamide, chloramine-b, chloramine-t,dichloramine t, n²-formylsulfisomidine, n⁴-β-d-glucosylsulfanilamide,mafenide, 4′-(methylsulfamoyl)sulfanilanilide, noprylsulfamide,phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine,succinylsulfathiazole, sulfabenzamide, sulfacetamide,sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine,sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole,sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfamerazine,sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine,sulfamethoxazole, sulfamethoxypyridazine, sulfametrole,sulfamidochrysoidine, sulfamoxole, sulfanilamide,4-sulfanilamidosalicylic acid, n⁴-sulfanilylsulfanilamide,sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine,sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine,sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea,sulfatolamide, sulfisomidine, sulfisoxazole) sulfones (e.g., acedapsone,acediasulfone, acetosulfone sodium, dapsone, diathymosulfone,glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid,p-sulfanilylbenzylamine, sulfoxone sodium, thiazolsulfone), and others(e.g., clofoctol, hexedine, methenamine, methenamineanhydromethylene-citrate, methenamine hippurate, methenamine mandelate,methenamine sulfosalicylate, nitroxoline, taurolidine, xibomol).

Antifungal Antibiotics:

Polyenes (e.g., amphotericin b, candicidin, dermostatin, filipin,fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin,nystatin, pecilocin, perimycin), others (e.g., azaserine, griseofulvin,oligomycins, neomycin undecylenate, pyrrolnitrin, siccanin, tubercidin,viridin).

Synthetic Antifungals:

Allylamines (e.g., butenafine, naftifine, terbinafine), imidazoles(e.g., bifonazole, butoconazole, chlordantoin, chlormidazole,cloconazole, clotrimazole, econazole, enilconazole, fenticonazole,flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole,omoconazole, oxiconazole nitrate, sertaconazole, sulconazole,tioconazole), thiocarbamates (e.g., tolciclate, tolindate, tolnaftate),triazoles (e.g., fluconazole, itraconazole, saperconazole, terconazole)others (e.g., acrisorcin, amorolfine, biphenamine,bromosalicylchloranilide, buclosamide, calcium propionate,chlorphenesin, ciclopirox, cloxyquin, coparaffinate, diamthazoledihydrochloride, exalarnide, flucytosine, halethazole, hexetidine,loflucarban, nifuratel, potassium iodide, propionic acid, pyrithione,salicylanilide, sodium propionate, sulbentine, tenonitrozole, triacetin,ujothion, undecylenic acid, zinc propionate).

Antineoplastic:

Antibiotics and analogs (e.g., aclacinomycins, actinomycin f₁,anthramycin, azaserine, bleomycins, cactinomycin, carubicin,carzinophilin, chromomycins, dactinomycin, daunorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, idarubicin,menogaril, mitomycins, mycophenolic acid, nogalamycin, olivomycines,peplomycin, pirarubicin, plicamycin, porfiromycin, puromycin,streptonigrin, streptozocin, tubercidin, zinostatin, zorubicin),antimetabolites (e.g. folic acid analogs (e.g., denopterin, edatrexate,methotrexate, piritrexim, pteropterin, Tomudex®, trimetrexate), purineanalogs (e.g., cladribine, fludarabine, 6-mercaptopurine, thiamiprine,thioguanine), pyrimidine analogs (e.g., ancitabine, azacitidine,6-azauridine, carmofur, cytarabine, doxifluridine, emitefur,enocitabine, floxuridine, fluorouracil, gemcitabine, tagafur).

Specific Antiinflammatory Agents Include, but Are Not Limited To:

Steroidal Antiinflammatory Agents:

21-acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, and triamcinolonehexacetonide.

Non-steroidal Antiinflammatory Agents:

Aminoarylcarboxylic acid derivatives (e.g., enfenamic acid, etofenamate,flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumicacid, talniflumate, terofenamate, tolfenamic acid), arylacetic acidderivatives (e.g., aceclofenac, acemetacin, alclofenac, amfenac,amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac,diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac,glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac,metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin,sulindac, tiaramide, tolmetin, tropesin, zomepirac), arylbutyric acidderivatives (e.g., bumadizon, butibufen, fenbufen, xenbucin),arylcarboxylic acids (e.g., clidanac, ketorolac, tinoridine),arylpropionic acid derivatives (e.g., alminoprofen, benoxaprofen,bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen,flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen,naproxen, oxaprozin, piketoprolen, pirprofen, pranoprofen, protizinicacid, suprofen, tiaprofenic acid, ximoprofen, zaltoprofen), pyrazoles(e.g., difenamizole, epirizole), pyrazolones (e.g., apazone,benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone,phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone,thiazolinobutazone), salicylic acid derivatives (e.g., acetaminosalol,aspirin, benorylate, bromosaligenin, calcium acetylsalicylate,diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate,imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholinesalicylate, 1-naphthyl salicylate, olsalazine, parsalmide, phenylacetylsalicylate, phenyl salicylate, salacetamide, salicylamide o-aceticacid, salicylsulfuric acid, salsalate, sulfasalazine),thiazinecarboxamides (e.g., ampiroxicam, droxicam, isoxicam, lomoxicam,piroxicam, tenoxicam), ε-acetamidocaproic acid, s-adenosylmethionine,3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine,a-bisabolol, bucolome, difenpiramide, ditazol, emorfazone, fepradinol,guaiazulene, nabumetone, nimesulide, oxaceprol, paranyline, perisoxal,proquazone, superoxide dismutase, tenidap, and zileuton.

The immunosuppressive agent is preferably from about 10 to 90% by weightof the implant. More preferably, the agent is from about 50 to about 80%by weight of the implant. In a preferred embodiment, the agent comprisesabout 50% by weight of the implant. In a preferred embodiment, the agentcomprises about 70% by weight of the implant.

The implants are preferably monolithic, i.e. having theimmunosuppressive agent homogeneously distributed through the polymericmatrix. In this patent, by homogeneously distributed we mean that theimmunosuppressive agent is distributed evenly enough that no detrimentalfluctuations in rate of immunosuppressive agent release occur because ofuneven distribution of the immunosuppressive agent in the polymermatrix. The selection of the polymeric composition to be employed willvary with the desired release kinetics, the location of the implant,patient tolerance, the nature of the transplant procedure and the like.Characteristics of the polymers will include biodegradability at thesite of implantation, compatibility with the agent of interest, ease ofencapsulation, water insolubility, and the like. Preferably, thepolymeric matrix will not be fully degraded until the drug load has beenreleased. The polymer will usually comprise at least about 10, moreusually at least about 20 weight percent of the implant. In oneembodiment, the implant comprises more than one polymer.

Biodegradable polymeric compositions which may be employed may beorganic esters or ethers, which when degraded result in physiologicallyacceptable degradation products, including the monomers. Anhydrides,amides, orthoesters or the like, by themselves or in combination withother monomers, may find use. The polymers may be condensation polymers.The polymers may be cross-linked or non-cross-linked, usually not morethan lightly cross-linked, generally less than 5%, usually less than 1%cross-linked. For the most part, besides carbon and hydrogen, thepolymers will include oxygen and nitrogen, particularly oxygen. Theoxygen may be present as oxy, e.g., hydroxy or ether, carbonyl, e.g.,non-oxo-carbonyl, such as carboxylic acid ester, and the like. Thenitrogen may be present as amide, cyano and amino. The biodegrablepolymers set forth in Heller, Biodegrable Polymers in Controlled DrugDelivery, in: CRC Critical Reviews in Therapeutic Drug Carrier Systems,Vol. 1. CRC Press, Boca Raton, Fla. (1987), may be used.

Of particular interest are polymers of hydroxyaliphatic carboxylicacids, either homo- or copolymers, and polysaccharides. Included amongthe polyesters of interest are polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. By employing the L-lactate or D-lactate, a slowly biodegradingpolymer is achieved, while degradation is substantially enhanced withthe racemate. Copolymers of glycolic and lactic acid are of particularinterest, where the rate of biodegradation is controlled by the ratio ofglycolic to lactic acid. The % of polylactic acid in the polylactic acidpolyglycolic acid (PLGA) copolymer can be 0-100%, preferably about15-85%, more preferably about 35-65%. In a particularly preferredembodiment, a 50/50 PLGA copolymer is used. The most rapidly degradedcopolymer has roughly equal amounts of glycolic and lactic acid, whereeither homopolymer is more resistant to degradation. The ratio ofglycolic acid to lactic acid will also affect the brittleness of in theimplant, where a more flexible implant is desirable for largergeometries. The size of the polymer particles is preferably about 1-100μm in diameter, more preferably about 5-50 μm in diameter, morepreferably about 9-12 μm in diameter, still more preferably about 10 μmin diameter.

Among the polysaccharides of interest are calcium alginate, andfunctionalized celluloses, particularly carboxymethylcellulose esterscharacterized by being biodegradable, water insoluble, a molecularweight of about 5 kD to 500 kD, etc. In one embodiment, the implantcomprises hydroxypropyl methylcellulose (HPMC).

Additionally, release modulators such as those described in U.S. Pat.No. 5,869,079 may be included in the implants. The amount of releasemodulator employed will be dependent on the desired release profile, theactivity of the modulator, and on the release profile of theimmunosuppressive agent in the absence of modulator.

Other agents may be employed in the formulation for a variety ofpurposes. For example, buffering agents and preservatives may beemployed. Water soluble preservatives which may be employed includesodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethylalcohol. These agents may be present in individual amounts of from about0.001 to about 5% by weight and preferably about 0.01 to about 2%.Suitable water soluble buffering agents that may be employed are sodiumcarbonate, sodium borate, sodium phosphate, sodium acetate, sodiumbicarbonate, etc., as approved by the FDA for the desired route ofadministration. These agents may be present in amounts sufficient tomaintain a pH of the system of between 2 to 9 and preferably 4 to 8. Assuch the buffering agent may be as much as 5% on a weight to weightbasis of the total composition. Electrolytes such as sodium chloride andpotassium chloride may also be included in the formulation. Where thebuffering agent or enhancer is hydrophilic, it may also act as a releaseaccelerator. Hydrophilic additives act to increase the release ratesthrough faster dissolution of the material surrounding the drugparticles, which increases the surface area of the drug exposed, therebyincreasing the rate of drug bioerosion. Similarly, a hydrophobicbuffering agent or enhancer dissolve more slowly, slowing the exposureof drug particles, and thereby slowing the rate of drug bioerosion.

The proportions of immunosuppressive agent, polymer, and any othermodifiers may be empirically determined by formulating several implantswith varying proportions. A USP approved method for dissolution orrelease test can be used to measure the rate of release (USP 23; NF 18(1995) pp. 1790-1798). For example, using the infinite sink method, aweighed sample of the drug delivery system is added to a measured volumeof a solution containing 0.9% NaCl in water, where the solution volumewill be such that the drug concentration is after release is less than5% of saturation. The mixture is maintained at 37° C. and stirred slowlyto maintain the implants in suspension. The appearance of the dissolveddrug as a function of time may be followed by various methods known inthe art, such as spectrophotometrically, HPLC, mass spectroscopy, etc.until the absorbance becomes constant or until greater than 90% of thedrug has been released.

The release kinetics of the drug delivery systems of the invention aredependent in part on the surface area of the implants. Larger surfacearea exposes more polymer to the eye, causing faster erosion anddissolution of the drug particles entrapped by the polymer. The size andform of the implant can be used to control the rate of release, periodof treatment, and drug concentration at the site of implantation. Largerimplants will deliver a proportionately larger dose, but depending onthe surface to mass ratio, may have a slower release rate. The implantsmay be particles, sheets, patches, plaques, films, discs, fibers,microcapsules and the like and may be of any size or shape compatiblewith the selected site of insertion, as long as the implants have thedesired release kinetics. Preferably, the implant to be inserted isformulated as a single particle. Preferably, the implant will notmigrate from the insertion site following implantation. The upper limitfor the implant size will be determined by factors such as the desiredrelease kinetics, location of the implant in the eye, toleration for theimplant, size limitations on insertion, ease of handling, etc. Forexample, the vitreous chamber is able to accommodate relatively largeimplants of varying geometries, having diameters of 1 to 3 mm. In apreferred embodiment, the implant is a cylindrical pellet (e.g., rod)with dimensions of about 2 mm×0.75 mm diameter. In another preferredembodiment, the implant is a cylindrical pellet (e.g., rod) withdimensions of about 1 mm×380 μm diameter. The implants will alsopreferably be at least somewhat flexible so as to facilitate bothinsertion of the implant in the eye and accommodation of the implant.The total weight of the implant is preferably about 50-5000 μg, morepreferably about 100-1000 μg. In one embodiment, the implant is about500 μg. In a particularly preferred embodiment, the implant is about1000 μg. In another particularly preferred embodiment, the implant isabout 120 μg. U.S. Pat. No. 5,869,079 further describes preferredimplant sizes for particular regions of the eye, as well as preferredsizes for particular implant shapes.

In a preferred embodiment, a solid bioerodible implant for reducing orpreventing transplant rejection in the eye is provided, comprising about50% by weight of dexamethasone, about 15% by weight of hydroxypropylmethylcellulose (HPMC) and about 35% by weight of polylacticpolyglycolic acid (PLGA).

In another preferred embodiment, a solid bioerodible implant forreducing or preventing transplant rejection in the eye is provided,comprising about 70% by weight of dexamethasone and about 30% by weightof polylactic polyglycolic acid (PLGA).

In another preferred embodiment, a solid bioerodible implant forreducing or preventing transplant rejection in the eye is provided,comprising about 50% by weight of dexamethasone and about 50% by weightof polylactic polyglycolic acid (PLGA).

The preferred supplier of PLGA is Boehringer Ingelheim and the preferredPLGA products are Resomer RG 502 and Resomer RG 502H.

In a preferred embodiment, the solid bioerodible implant includes about50% by weight of dexamethasone, about 15% by weight of hydroxypropylmethylcellulose (HPMC) and about 35% by weight of Resomer RG 502H PLGA.

In a preferred embodiment, the solid bioerodible implant includes about60% by weight of dexamethasone, about 30% by weight of Resomer RG 502HPLGA, and about 10% by weight of Resomer RG 502 PLGA.

Methods for Making the Implants

Various techniques may be employed to produce the implants. Usefultechniques include phase separation methods, interfacial methods,extrusion methods, compression methods, molding methods, injectionmolding methods, heat press methods and the like.

Choice of the technique and manipulation of the technique parametersemployed to produce the implants can influence the release rates of thedrug. Room temperature compression methods result in an implant withdiscrete microparticles of drug and polymer interspersed. Extrusionmethods result in implants with a progressively more homogenousdispersion of the drug within the polymer, as the production temperatureis increased. When using extrusion methods, the polymer and drug arechosen to as to be stable at the temperatures required formanufacturing, usually at least about 85° C. Extrusion methods usetemperatures of about 25° C. to about 150° C., more preferably about 65°C. to about 130° C. Generally, compression methods yield implants withfaster release rates than extrusion methods, and higher temperaturesyield implants with slower release rates.

In a preferred embodiment, compression methods are used to produce theimplants of the invention. Preferably, compression methods use pressuresof 50-150 psi, more preferably about 70-80 psi, even more preferablyabout 76 psi, and use temperatures of about 0° C. to about 115° C., morepreferably about 25° C. In another preferred embodiment, extrusionmethods are used. Preferably, implants produced by extrusion methods areheated to a temperature range of about 60° C. to about 150° C. fordrug/polymer mixing, preferably about 85° C., preferably about 130° C.,for a time period of about 0 to 1 hour, 0 to 30 minutes, 5-15 minutes,preferably about 10 minutes, preferably about 0 to 5 min, preferablyabout 1 hour. Preferably, the implants are then extruded at atemperature of about 60° C. to about 130° C., preferably about 95° C.,preferably about 85° C., preferably about 75° C.

U.S. Pat. No. 4,997,652 further describes suitable methods for makingthe implants of the invention, and is herein incorporated by referencein its entirety.

Kit for the Administration of the Implants

In another aspect of the invention, a kit for treating or preventingtransplant rejection in the eye is provided, comprising a bioerodibledrug delivery system comprising an immunosuppressive agent and abioerodible polymer, wherein the drug delivery system is designed to beimplanted in the eye. The kit may also include instructions for use.

The bioerodible drug delivery systems as described herein are suitablefor use in the kits of the invention. In a preferred embodiment, theimmunosuppressive agent is dexamethasone.

The invention is further described by the following nonlimitingexamples.

EXAMPLES Example 1 Effect of Dexamethasone Implant in Animal PenetratingKeratoplasty Model

The objective of this study was to determine the efficacy of sustainedrelease intraocular dexamethasone implanted in the anterior chamber ofthe rat eye at the end of cornea transplant surgery and compare it withlocal eye drop therapy. The approximately 120 μg dexamethasone implantcontained about 15% HPMC, 35% PLGA and 50% dexamethasone, and wasprepared and tested in vitro as described in U.S. Pat. No. 5,869,079(See Example 1), which is specifically incorporated herein by referencein its entirety.

In order to create a very high risk of cornea rejection, a xenograftmodel was chosen. Mouse cornea from 12 mice of either sex were used asdonor tissues for rat.

Eighteen rats of either sex were used in the study. They were dividedinto 3 groups. Group #1—6 animals received treatment with thedexamethasone implant, Group #2—received treatment with topical steroidand Group #3—control group (without any treatment). Animals werefollowed up to 8 weeks. After euthanasia eyes were sent forhistopathology examination.

TABLE 1 Study design Animal # Group # Eye Treatment 1 1 OD Dex implant 21 ″ ″ 3 1 ″ ″ 4 1 ″ ″ 5 1 ″ ″ 6 1 ″ ″ 7 2 ″ Dex eye drops 8 2 ″ ″ 9 2 ″″ 10 2 ″ ″ 11 2 ″ ″ 12 2 ″ ″ 13 3 ″ Control (no treatment) 14 3 ″ ″ 15 3″ ″ 16 3 ″ ″ 17 3 ″ ″ 18 3 ″ ″

Supplies: 0.5% Ophthaine Solution, euthasol solution, ketamine HCl,xylazine

Animal Preparation and Surgical Procedure

Obtaining donor corneas: Each mouse was weighed and anesthetized. Whileunder anesthesia, the ophthalmologist collected all donor cornea buttonsfrom mice using trephine. After the procedure mice were euthanized by alethal dose of Euthasol.

Penetrating keratoplasty (PKP): Each rat was weighed and anesthetized.Using 2.5 mm trephine an initial incision was made in the middle ofcornea. The incision was finished using corneal scissors. The anteriorchamber (AC) was held using balanced salt solution (BSS). The donorcornea button was attached to the host cornea with 8 interrupted sutureswith 11-0 nylon. Before closing the anterior chamber, the dexamethasoneimplant was implanted into the AC of the first 6 animals.

All eighteen rats survived the procedure. All eyes were examined by anophthalmologist by slit lamp and all signs of cornea rejection(neovascularization, edema, etc.) were recorded.

In group #2, all animals received 2 drops of Dexamethasone eye dropsevery day, until the rejection occurred.

Based on clinical observation, rejection of cornea in Group #3 (control)occurred in the first few days after surgery, and by week one 80% ofdonors' cornea were rejected, by week two 100%. Corneas were showingheavy neovascularization in the first few days followed by corneal edemaand total rejection. Group #2 (topical Dexamethasone eye drops) hadsimilar signs observed in this group with some delay. 20% of cornearejection occurred by week two, 50% by week three, and 80% by week six.At the time of euthanasia (week 8) only 20% were not completelyrejected.

However, in group #1, treated with the dexamethasone implant, thecorneas did not show any signs of rejection (neovascularization, edema).In all eyes the corneas stayed clear. By the end of the study (weekeight) the graft survival was 100%.

Histopathology examination confirmed the clinical observations. In Group#3 heavy inflammation was observed in AC, cornea endothelium, also inthe stroma, and some in the epithelium. Corneas also showed edema due todestroyed endothelial cells.

In Group #2 similar findings were observed.

In Group #1, inflammation was totally suppressed by the dexamethasoneimplant.

The entire clinical and histological finding in this study clearlydemonstrated that intraocular sustained release Dexamethasone canprevent corneal rejection in a high-risk xenograft model.

Example 2 Manufacture and in vitro Testing of Bioerodible DexamethasonePosterior Segment Drug Delivery System (DEX PS DDS®)

2100 mg of dexamethasone powder (Upjohn) (particle sizes less than 10 μmin diameter) were mixed with 900 mg of 50/50 polylactic acidpolyglycolic acid (PLGA) (particle sizes approximately 9-12 μm indiameter) at ambient temperature. A small Teflon® tube was filled with900-1100 μg of the above mixture, and placed directly on the die cavity.The powder was pushed out of the tubing into the die cavity with astainless steel wire and the tube and wire were removed from the die.The powder was pressed using a tablet press (approximately 76 psi),ejected with the ejector switch, and removed with tweezers. Theresulting pellet was approximately 2 mm×0.75 mm.

Release of dexamethasone from the DEX PS DDS® system was measured. OneDDS was placed in a glass vial filled with receptor medium (0.9% NaCl inwater). To allow for “infinite sink” conditions, the receptor mediumvolume was chosen so that the concentration would never exceed 5% ofsaturation. To minimize secondary transport phenomena, e.g.concentration polarization in the stagnant boundary layer, the glassvial was placed into a shaking water bath at 37° C. Samples were takenfor HPLC analysis from the vial at defined time points. The HPLC methodwas as described in USP 23(1995) pp.1791-1798. The concentration valueswere used to calculate the cumulative release data, as shown in Table 2.

TABLE 2 DEX PS DDS ® In vitro Release Day % Total Release 1 10.1 2 16.47 39.4 14 55.5 21 69.3 28 80.7 35 88.1

Table 2 shows an almost linear in vitro release of dexamethasone over aone month period of time.

Example 3 In vivo Testing of DEX PS DDS® in Rabbits

One DEX PS DDS® per eye was implanted into the vitreous of four rabbitswith forceps. The in vivo vitreous concentrations of dexamethasone ineach of the fore eye were monitored by vitreous sampling. For example,at day 2 the concentrations measured were 0.03 μg/ml, 0.1 μg/ml, 0.33μg/ml and 0.19 μg/ml. The concentrations in each of the four eyes weremeasured on days 2, 7, 21, 28 and 35; the results are summarized inTable 3. The volume of rabbit eyes is approximately 60-70% percent thatof human eyes.

TABLE 3 In vivo concentrations of dexamethasone (DDS placed withforceps) Day μg/ml 2 0.16 ± 0.13 7 0.15 ± 0.16 21 0.08 ± 0.07 28 0.005 ±0.01  35 0.037 ± 0.03 

The same DDS was tested in vivo in rabbits, wherein the DDS was placedto a depth of about 5-10 mm in the vitreous with trocar. The levels ofdexamethasone in vitreous are shown in Table 4.

TABLE 4 In vivo concentrations of dexamethasone (DDS placed with trocar)Sample ID 5293-D 5295 = D 5293-S 5295-S 5304-D 5306-D 5304-S 5306-SHours Sample Conc., μg/ml Avg SD  2 0.56 3.07 1.82 1.77  4 5.48 6.956.22 1.04  6 2.08 5.15 3.62 2.17 24 2.33 2.69 2.51 0.25 DDS wt. Dex wt.Dex μg/mL Animal#\day μg μg 2 7 14 21 28 35 21427-D 990 693 2.29 21427-S1023 715.1 1.56 21433-D 804 562.8 1.2 21433-S 1057 739.9 0.77 21428-D1003 702.1 9.26 21428-S 1025 717.5 0.35 21434-D 863 604.1 3.31 21434-S1106 774.2 0.84 21429-D 1013 709.1 n/a 21429-S 927 648.9 0.19 21435-D1104 772.8 0.43 21435-S 941 658.7 0.11 21432-D 860 692 0.43 21432-S 941685.7 1.72 21436-D 1010 707 0.31 21436-S 1054 737.8 0.13 21431-D 996697.2 0.52 21431-S 918 642.6 1.15 21437-D 1049 732.9 0.19 21437-D 1075752.5 0.48 21430-D 994 695.8 0.06 21430-S 1086 760.2 0.18 21438-D 974681.8 0.03 21438-S 831 581.7 8.35 Ave. 985.17 694.43 1.46 3.44 0.24 0.650.59 2.16 *Unable to determine due to insufficient sample

The data indicate that the DEX PS DDS® releases dexamethasone to thevitreous in concentrations above 0.01 μg/ml for an extended period oftime. Further, the data indicate that placement of the device withtrocar results in much higher levels of drug release than with placementwith forceps, most likely due to placement of the device deeper withinthe vitreous. The data at two, four, six, and 24 hours in Table 4 showsan initial spike of drug release.

Example 4 Manufacture and in vitro Testing of 50/50 Dexamethasone/PLGAPosterior Segment Drug Delivery System

2.5 g of PLGA (particle sizes approximately 9-12 μm in diameter) wereplaced in a mixing vessel. The vessel was placed in the oven (130° C.)for ten minutes. 2.5 g of dexamethasone (particle sizes less thanapproximately 10 μm in diameter) were added to the vessel, and thevessel was returned to the oven for 10 minutes. The PLGA/dexamethasonemixture was mixed well, the blend loaded into a barrel, and 650-790 μmdiameter filaments extruded. The resulting filaments were cut intolengths of approximately 0.94 and 1.87 mm for the 500 μg and 1000 μgformulations, respectively.

Release of dexamethasone from the 50/50 dexamethasone/PLGA DDSformulations were measured. One DDS was placed in a glass vial filledwith receptor medium (0.9% NaCl in water). To allow for “infinite sink”conditions, the receptor medium volume was chosen so that theconcentration would never exceed 5% of saturation. To minimize secondarytransport phenomena, e.g. concentration polorization in the stagnantboundary layer, the glass vial was placed into a shaking water bath at37° C. Samples were taken for HPLC analysis from the vial at definedtime points. The HPLC method was as described in USP 23(1995)pp.1791-1798. The concentration values were used to calculate thecumulative release data, as shown in Tables 5 and 6.

TABLE 5 In vitro release of 50% Dex-PS (0.5 mg formulation) Dex μg DayRelease/day % Total release 50% Dex PS 0.5 mg system replicate 1 1 3.001.41 7 1.99 7.93 13 0.90 13.43 20 1.79 30.21 27 1.54 49.77 34 1.93 80.5241 0.24 85.05 48 0.24 90.38 55 0.10 93.00 62 0.15 97.44 69 0.07 99.84 760.07 102.25 50% Dex PS 0.5 mg system replicate 2 1 6.00 2.17 7 1.66 6.3813 0.99 11.05 20 1.21 19.82 27 2.29 42.23 34 2.34 71.05 41 0.44 77.54 480.29 82.61 55 0.14 85.34 62 0.20 89.80 69 0.10 92.21 76 0.06 84.38 50%Dex PS 0.5 mg system replicate 3 1 5.70 3.27 7 1.11 7.71 13 0.83 13.8320 0.05 14.47 27 1.63 39.63 34 1.52 69.26 41 0.21 74.10 48 0.19 79.23 550.08 81.69 62 0.14 86.58 69 0.07 89.46 76 0.06 92.26

TABLE 6 In vitro release of 50% Dex-PS (1 mg formulation) Dex μg DayRelease/day % Total release 50% Dex PS 1 mg system replicate 1 1 6.901.28 7 3.48 5.78 13 1.93 10.43 20 3.46 23.22 27 3.74 41.89 34 3.94 66.8341 1.79 80.17 48 1.28 91.49 55 0.21 93.59 62 0.24 96.39 69 0.11 97.85 760.09 99.11 50% Dex PS 1 mg system replicate 2 1 3.90 0.71 7 2.26 3.62 131.66 7.57 20 3.14 19.09 27 4.32 40.48 34 4.06 65.77 41 1.61 77.90 481.34 89.70 55 0.19 91.60 62 0.23 94.18 69 0.10 95.50 76 0.09 96.78 50%Dex PS 1 mg system replicate 3 1 4.50 0.91 7 2.16 3.98 13 1.69 8.42 201.25 13.48 27 3.88 34.67 34 3.53 58.97 41 1.85 74.28 48 0.88 82.85 550.19 84.94 62 0.26 88.15 69 0.11 89.75 76 0.10 91.26

Example 5 In vivo Testing of 50/50 Dexamethasone/PLGA 1 mg Formulationsin Rabbits

One 50/50 dexamethasone/PLGA 1 mg formulation DDS per eye was implantedinto the vitreous of 6 rabbits using a trocar. The DDS was loaded intothe trocar, a hole was punched through the sclera, the trocar insertedthrough the hole, and the trocar plunger depressed to insert the DDSinto the vitreous. In vivo vitreous concentrations of dexamethasone weremonitored, as shown in Table 7.

TABLE 7 In vivo vitreous concentrations of dexamethasone Sample ID5293-D 5295 = D 5293-S 5295-S 5304-D 5306-D 5304-S 5306-S Hours SampleConc., μg/ml Avg SD  2 1.38 1.69 1.54 0.22  4 2.16 0.96 0.47 0.37  60.73 0.21 0.47 0.37 24 0.57 0.74 0.66 0.12 Dex μg/mL Animal#\day 7 21 3549 63 2953-D 0.5 0.58 2953-S 0.11 0.69 2952-D 0.13 1.2 2952-S 0.12 0.552946-D 0.19 2.55 2946-S *3 0.14 2949-D *5.44 0.28 2949-S 0.0248 0.012982-D 1.087 2982-S 0.058 2983-D 0.018 2983-S 0.045 Ave. 0.22 2.16 0.300.76 0.75 *High level was due to the surgical artifact

The data indicate that the 50/50 dexamethasone/PLGA DDS releasesdexamethasone to the vitreous in concentrations above 0.01 μg/ml for anextended period of time. The data at two, four, six, and 24 hours inTable 7 shows an initial spike of drug release, due to drug which isunencapsulated by the delivery system.

Modifications of the above described modes for carrying out theinvention that are obvious to those of ordinary skill in the surgical,pharmaceutical, or related arts are intended to be within the scope ofthe following claims.

1. A method for preventing transplant rejection in an eye of anindividual, comprising: a) performing an ocular transplant procedure onan eye of an individual, and b) implanting in the eye a bioerodible drugdelivery system comprising a steroidal immunosuppressive agent and abioerodible polymer, the steroidal immunosuppressive agent beingeffective in preventing transplant rejection when released into the eyefrom the drug delivery system.
 2. An intraocular, bioerodible drugdelivery system comprising particles of a drug effective when releasedinto an eye of an individual who has undergone or is undergoing anocular transplant procedure in reducing or preventing ocular transplantrejection, a polylactic acid polyglycolic acid (PLGA) copolymer, andincluding no added release modifier, wherein the system is effective inreleasing the drug into the eye over a period of at least about 3 weeksin an amount effective in reducing or preventing ocular transplantrejection, wherein the intraocular bioerodible drug delivery system is asingle pellet or a single extruded filament.
 3. The drug delivery systemof claim 2, wherein the drug is present as particles in the bioerodiblepolymer.
 4. The drug delivery system of claim 2, wherein the drug is animmunosuppressive agent.
 5. The drug delivery system of claim 4, whereinthe immunosuppressive agent is selected from the group consisting ofdexamethasone, cyclosporine A, azathioprine, brequinar, gusperimus,6-mercaptopurine, mizoribine, rapamycin, tacrolimus (FK-506),denopterin, edatrexate, methotrexate, piritrexim, pteropterin,raltitrexed, trimetrexate, cladribine, fludarabine, 6-mercaptopurine,thiamiprine, thiaguanine, ancitabine, azacitidine, 6-azauridine,carmofur, cytarabine, doxifluridine, emitefur, enocitabine, fluxuridine,fluorouracil, gemcitabine, egafur, flucinolone, triamcinolone,anecortave acetate, fluorometholone, medrysone, and prednisolone.
 6. Thedrug delivery system of claim 4, wherein the immunosuppressive agent isdexamethasone.
 7. The drug delivery system of claim 4, wherein theimmunosuppressive agent is cyclosporine A.
 8. The drug delivery systemof claim 2, which is effective when implanted into an anterior chamberof an eye of an individual who has undergone or is undergoing an oculartransplant procedure to reduce or prevent ocular transplant rejection.9. The drug delivery system of claim 2, which is effective whenimplanted into a vitreous cavity of an eye of an individual who hasundergone or is undergoing an ocular transplant procedure to reduce orprevent ocular transplant rejection.
 10. The drug delivery system ofclaim 2, wherein the drug is present in an amount in a range of about10% to 90% by weight.
 11. The drug delivery system of claim 2, whereinthe drug is present in an amount in a range of about 50% to about 80% byweight.
 12. The drug delivery system of claim 2, wherein the bioerodiblepolymer is a polyester.
 13. An intraocular, bioerodible drug deliverysystem comprising dexamethasone effective when released into an eye ofan individual who has undergone or is undergoing an ocular transplantprocedure to reduce or prevent ocular transplant rejection, and abioerodible copolymer, and including no release modifier, wherein thedexamethasone is present as particles in the bioerodible copolymer,wherein the intraocular, bioerodible drug delivery system is a singlepellet or a single extruded filament.
 14. The drug delivery system ofclaim 13, which can be implanted in an eye of an individual who hasundergone or is undergoing an ocular transplant procedure to releasedexamethasone in the eye over a period of at least about 3 weeks in anamount effective to reduce or prevent ocular transplant rejection. 15.The drug delivery system of claim 13, which can be implanted into ananterior chamber of an eye of an individual who has undergone or isundergoing an ocular transplant procedure to reduce or prevent oculartransplant rejection.
 16. The drug delivery system of claim 13, whichcan be implanted into a vitreous cavity of an eye of an individual whohas undergone or is undergoing an ocular tranplant procedure to reduceor prevent ocular transplant rejection.
 17. The drug delivery system ofclaim 13, wherein dexamethasone is present in an amount in a range ofabout 10% to 90% by weight.
 18. The drug delivery system of claim 13,wherein dexamethasone is present in an amount in a range of about 50% to80% by weight.
 19. The drug delivery system of claim 13, wherein thebioerodible copolymer is a polyester.
 20. The drug delivery system ofclaim 13, wherein the bioerodible copolymer is a polyactic acidpolyglycolic acid (PLGA) copolymer.
 21. An intraocular, bioerodible drugdelivery system comprising a steroid effective in preventing or reducingneovascularization in an eye prone to neovascularization, and apolyactic acid polyglycolic acid (PLGA) copolymer thereby forming animplant for placement in the interior of an eye prone toneovascularization.
 22. The drug delivery system of claim 21 wherein thesteroid is dexamethasone.
 23. The drug delivery system of claim 21 whichincludes no release modifier.
 24. The drug delivery system of claim 21,wherein the steroid comprises about 10% to 90% of the weight of the drugdelivery system.
 25. The drug delivery system of claim 21, wherein thesteroid is the sole active ingredient for preventing or reducing saidneovascularization.
 26. An intraocular, bioerodible drug delivery systemcomprising a steroid effective in preventing or reducingneovascularization in an eye prone to neovascularization, and apolylactic acid polyglycolic acid (PLGA) copolymer.
 27. The intraocular,bioerodible drug delivery system of claim 26, wherein the steroidcomprises about 50% to about 80% by weight of the drug delivery system.28. The intraocular, bioerodible drug delivery system of claim 26wherein the steroid is present as particles homogenously distributed inthe bioerodible polymer.
 29. The drug delivery system of claim 26,wherein the implant can be placed in the vitreous of the eye.
 30. Thedrug delivery system of claim 21, wherein the steroid is ananti-inflammatory steroid.
 31. A method for treating neovascularizationin an eye of an individual, comprising: implanting in an eye prone toneovascularization a bioerodible drug delivery system comprising animmunosuppressive agent and a polyactic acid polyglycolic acid (PLGA)copolymer.
 32. An intraocular, bioerodible drug delivery systemcomprising particles of a drug, a polyactic acid polyglycolic acid(PLGA) copolymer, wherein the system is effective in releasing the druginto the eye over a period of at least about 3 weeks, and wherein theintraocular, bioerodible drug delivery system is a single pellet or asingle extruded filament.